2 Overview of PresentationFor more presentations and information visitOverview of PresentationPain and the Pain managementEndogenous Opioid PeptidesOpioid receptors and effectsChemical Structure and Binding Features of Opioid AnalgesicsTypes of Opioid Analgesics

3 For more presentations and information visit http://www. pharmaxchangeWhat is Pain?Pain is a crucial aspect of the body’s defense mechanismsPain “is a part of a rapid warning relay instruction of the motor neurons of the central nervous system to minimize detected physical harm.”Pain can be defined as a somatic sensation of acute discomfort, a symptom of some physical hurt or disorder, or even emotional distress.Pain can be classified into two types:Acute painChronic pain

4 Acute Pain and Chronic PainFor more presentations and information visitAcute Pain and Chronic PainAcute pain is short-term pain or pain with an easily identifiable causeAcute pain “is the body's warning of present damage to tissue or disease. It is often fast and sharp followed by aching pain. Acute pain is centralized in one area before becoming somewhat spread out. This type of pain responds well to medications.”Chronic pain is pain that last much longer than pain normally would with a particular injury.Chronic pain can be constant or intermittent and is generally harder to treat than acute pain.Pain can also be grouped by its source and related pain detecting neurons such as cutaneous pain, somatic pain, visceral pain, and neuropathic painOpioid Analgesics can be used to treat many types of pain

5 For more presentations and information visit http://www. pharmaxchangePain SignalingThere are certain nociceptive receptors present on on the skin and various organs of the body.When any traume or stimuli for pain approaches, certain substances are released at the site, causing the signalling from sensory neurons.These neurons release excitatory neurotransmitters which relay signals from one neuron to another.“The signals are sent to the thalamus, in which pain perception occurs. From the thalamus, the signal travels to the somatosensory cortex in the cerebrum, at which point the individual becomes fully aware of the pain.”

6 For more presentations and information visit http://www. pharmaxchange

7 For more presentations and information visit http://www. pharmaxchangeWhat is Analgesia?Analgesia simply means the absence of pain without loosing consciousness.“The analgesia system is mediated by 3 major components : the periaquaductal grey matter (in the midbrain), the nucleus raphe magnus (in the medulla), and the pain inhibitory neurons within the dorsal horns of the spinal cord, which act to inhibit pain-transmitting neurons also located in the spinal dorsal horn.”These areas are the areas in which the chemical mechanisms of opioid analgesics will take place

8 Locations involved in Pain Signaling and AnalgesiaFor more presentations and information visitLocations involved in Pain Signaling and Analgesia

9 For more presentations and information visit http://www. pharmaxchangeWhat is an Opioid?Opioids are drugs derived from or related to the OpiumOpium is derived from the juice of the opium poppy, Papaver somniferumOpium contains over twenty distinct alkaloids (morphine was the first alkaloid of opium to be isolated in 1806)By the late 19th century use of these “pure” opium derivatives spread throughout the medical world, however, the method by which these drugs works was unknown.

10 Endogenous Opioid PeptidesFor more presentations and information visitEndogenous Opioid PeptidesIn 1973 researchers determined the existence of opiate binding sites in the brain through the use of radioligand-binding assaysIn 1975, an endogenous opiate-like factor called enkephalin was found and shortly after this two more classes of endogenous opiate peptides were isolated, the dynophorins and the endorphins.“Endogenous opioid peptides are the naturally occurring ligands for opioid receptors.”These peptides are produced by the pituitary gland and by the hypothalamusOpioid peptides are found in the central nervous system mainly in limbic and brainstem areas associated with pain reception, and the certain areas of the spinal cord. Their distribution corresponds to “areas of the human brain where electrical stimulation can relieve pain .”

11 Endogenous Opioid PeptidesFor more presentations and information visitEndogenous Opioid PeptidesThese natural peptides work as ligands that interact with their specific receptors causing structural changes that result in other changes in the effected neuron such as the opening or closing of ion gated channels or the activation or deactivation of certain enzymes.Opioid peptides work by modulating the release and uptake of specific neurotrasmitters in the neurons they are found. This alteration of neurochemical balance creates a vast amount of possible physiological effects, one of which is analgesia.All of the endogenous opioid peptides are derived from a corresponding precursor proteins and all share a common amino- terminal sequence which is called the “opioid motif.”

12 For more presentations and information visit http://www. pharmaxchangeThe Opioid ReceptorsShortly after the discovery and observance of endogenous opioid peptides, multiple classes of unique opioid receptors were foundTypes:the mu receptor,the delta receptor,the kappa receptor, andthe ORL-1 receptor.The receptors are found on cell membranes of cells in the nervous system (neurons) and are found in unique distributions and have different effects.

13 For more presentations and information visit http://www. pharmaxchangeThe μ-receptorMorphine and its analogues bind most strongly to this receptor and in fact most used opioid analgesic drugs are selective for this specific receptor type.Location:They are seen in significant amounts in all areas of the central nervous system associated with pain controlTypes:There are two subtypes of the mu-receptor.1. μ1-receptors: analgesic activities and the 2. μ2-receptors: effects of respiratory depression and constipation.

14 The μ-receptor Mechanism:For more presentations and information visitThe μ-receptorMechanism:When an opioid binds to the mu-receptor it induces a change in shape which in turn induces a change in the ion channels of the associated cell membraneThe mu-receptor opens up the ion channel allowing potassium ions to flow out of the cell causing hyperpolarization of the membrane potential. This hyperpolarization causes it to become extremely difficult for an action potential to be reached and therefore the firing of the neuron become far less frequent and the neurons excitability decreases.The release of potassium ions also causes less calcium ions to enter the terminal end of the neuron. This is where neurotransmitters are stored and as a result this significantly reduces neurotransmitter release.These effects of a ligand binding to a mu-receptor essentially turn off the neuron and in doing so block the relaying of pain signals from pain receptors.

15 The μ-receptor Effects produced by the stimulation of mu-rec.:For more presentations and information visitThe μ-receptorEffects produced by the stimulation of mu-rec.:When and opioid binds to the mu-receptor it produces the effects of analgesia. The mu-receptor is also associated with other effects such as “sedation, reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils) and decreased bowel motility often leading to constipation.Respiratory depression is considered the deadly side effect of opioid analgesic drugs. It is the cause of death in all overdose cases.

16 For more presentations and information visit http://www. pharmaxchangeSynapses between afferent nociceptive neurons and secondary ascending neurons relay pain signals to the brain. The entry of Ca2+ into the pre-synaptic primary neuron and the release of K+ from the post-synaptic secondary neuron are processes involved in signal transmission across the synapse.

17 For more presentations and information visit http://www. pharmaxchangeOpioids binding to ion channel associated m receptors inhibit the influx of calcium ions into the pre-synaptic terminal and increase the outflow of potassium ions from the post-synaptic membrane. This has the effect of reducing the release of the neurotransmitter glutamate and hyperpolarising the post-synaptic membrane. Synaptic transmission is inhibited.

18 For more presentations and information visit http://www. pharmaxchangeThe κ-receptorThe kappa receptor is very different from the mu-receptor in the fact that there are not many significant agonist of the kappa receptor knownTypes:There are three subtypes of the kappa receptor however the difference between these subtypes is not clearly known.Effects :The kappa receptor is associated directly with analgesia and sedation but with none of the undesired side effects associated with the mu receptor.Because of this, it is an area of focus in current research and shows promise in the development of a safer analgesic.

19 The κ-receptor Mechanisn:For more presentations and information visitThe κ-receptorMechanisn:When and agonist or ligand binds to the kappa receptor it induces a conformational change that results directly in the closing of the calcium ion channels in the terminal of the neuron and the neuron can not relay pain messages.Diff. from mu-rec:Another difference between the kappa and mu receptors is that the kappa receptors only effect nerves that relay “pain produced by non-thermal stimuli,” and mu receptors inhibit all pain signals.

20 For more presentations and information visit http://www. pharmaxchangeThe δ-receptorThe delta receptor is the strongest binding site of the body’s natural pain killer, the class of opioid peptides called the enkephalins.Morphine and other commonly used opioid analgesics also bind to this receptor strongly and act as an agonist much like they do with the mu receptor.Location:The delta receptor is found in larger cells than the other receptors and seems to be important in spinal analgesia. Present in spinal and limbic areas,so responsible for reinforcement and dependence actions..

21 The δ-receptor Mechanism:For more presentations and information visitThe δ-receptorMechanism:The delta receptor is a G-protein linked receptor. When an agonist binds to the delta receptor is induces a conformational change that causes the activation of a specific G-protein.This G-protein “inhibits the membrane bound enzyme adenylate cyclase and prevents the synthesis of cAMP. The transmission of the pain signal requires cAMP to act as a secondary messenger, and so inhibition of this enzyme blocks the signal.”Also causes hyperpolarization by increase k+-efflux.Effects:Most effects are similar to mu-rec, however kappa appears to have some opposite effects in certain areas.

22 For more presentations and information visit http://www. pharmaxchangeThe ORL-1 receptorThe ORL-1 receptor or the “orphan” receptor was very recently discovered.The natural opioid peptide that is a ligand for this receptor is nociceptin which is also called orphaninFQ.Whole system is called N/OFQ system.Effects:The ORL-1 receptor is associated with many different biological effects such as memory processes, cardiovascular function, and renal function.Capable of opposing mu-rec mediated analgesia as well as modulating memory and learning processes.It is thought to have effects on dopamine levels and is associated with neurotransmitter release during anxiety.

25 For more presentations and information visit http://www. pharmaxchangeStructure of OpioidsIn order to examine important structural features of Opioid analgesics, which are all derived from the opiate structure, we will refer to the structure of morphine, the first identified alkaloid.

26 For more presentations and information visit http://www. pharmaxchangeStructure of OpioidsThe structure of morphine consists of five rings forming a T-shaped moleculeThe important binding groups on morphine are the phenol, the aromatic ring, and the ionized amine. These groups are found in all Opioid analgesics.. “A free phenol group is crucial for analgesic activity.” The aromatic ring of the opiate also seems to be integral to its function as compounds that lack the aromatic ring show no analgesic activity. The ionized amine also plays an important role in its activity and is common in opioid structure. In experiments where the Nitrogen was replaced by a Carbon no analgesic activity was found. It interacts with certain analgesic receptors in its ionized form.

29 A.Opoid-agonists: Naturally occuring: i.phenanthrenes:For more presentations and information visitA.Opoid-agonists: Naturally occuring: i.phenanthrenes::Morphine:Morphine is the golden standard among opioid analgesics to which the structure and strengths of all other drugs are comparedIt is the primary ingredient in opium and was isolated in 1806Morphine has strong binding affinity for the mu and delta opioid receptors and some weak affinity for the kappa receptor

30 MORPHINE Pharmacokinetics: i/v, S/C, I/M Oral bioavailability is low.For more presentations and information visitMORPHINEPharmacokinetics:i/v, S/C, I/MOral bioavailability is low.T1/ hrs, duration of analgesia is 4-5 hrs.Absorption: from GIT is usually slow and erratic so not given orally .Significant first-pass metabolism in liverDistributed in highly perfused aread as liver, kidney ,brain, lungs and to lower conc in skeletal muscles (serving as a reservior)Only small amount cross BBB.Enters in the foetus,so shouldn’t be used in pregnancy.Metabolized in liver to 6 glucuronic acid(M6G),an active metabolite with more potent analgesic activity, and M3G,neuroexcitatory.Excreted via glucuronide conjugate into the urine.

31 Pharmacological effects:For more presentations and information visitPharmacological effects:1.Miosis:Due to excitation of autonomic segment of eye.2.Respiration:Depressant effect. Due to direct effect on the brain-stem resp centres.Death is always due to resp.depression.3.Cough:Depress the cough,in part dur to direct effect on the cough centre in medulla.4.CVS:orthostatic hypotension and fainting.(due to the release of histamine and depression of vaso-motor centre)5.Nausea and vomitting:By triggering CTZ(may involve vestibular component)Gastric stasis

32 Pharmacological effects….For more presentations and information visitPharmacological effects….6.GIT:Decrease HCl secretion.(indirectly due to the increased secretion of somatostatins from pancreas and reduces release of Ach).Diminish biliary, pancreatic and intestinal secretions. resting tone increased and spasms observed.Propulsive peristaltic movements in colon are abolished resulting in morphine-induced constipation.Along with this,inattention of the stimuli for defecation owing to central effects.resulting in constipation.no tolerence to this dev.Biliary colics. Due to increased pressure due to the constriction of sphinctor of oddi7.Ureter and urinary-bladder:inhibit the urinary voiding reflexes and tone of sphinctor and vol of bladder increase.8.Uterus:may prolong labour,restoring tone, freq. and amplitude to normal.(if hyperactive by oxytocin)

33 Pharmacological effects…..For more presentations and information visitPharmacological effects…..9.Skin:Flushing of face,neck and upper thorax.(histamine release).10.Immune-system:May modulate the actions of immune sys, by effects on lymphocyte proliferation ,a.body prod, and chemotaxis.natural killer cell cytolytic activity and lymphocyte proliferative responses may be inhibited by these.(med by sympathetic sys. And a/f prolong use by hypothalmic- pituitaryadrenal sys.{corticosteroids})11.Neuroendocrine effects:Acts on hypothalamus to inhibit release of.GnRH ,Corticotropic releasing factor.—low conc of circulating LH, FSH,ACTH.as a result of low conc. Of pituitary trophic hormones,the conc. Of testosterone and cortisol decrease.It may increase the release of prolactin,probably by inhibiting the dopaminergic inhibition of its secretion.Mu-agonists seems to have antidiuretic effects.(inc. release of ADH).

34 Pharmacological effects…..For more presentations and information visitPharmacological effects…..12..Analgesia.Opoid rec.on the terminal of pri afferent nerves mediate inhibition of n/t release.(substance-P)post-synaptic inhibition of interneuons that conveys nociceptive info to higher brain areas13.Euphoria:(septal nuclei)Patnts in pain experience a pleasant feelingPtnts not in pain feels dysphoria(malaise)14.Sedation:(hebenula)drowsiness,clouding of mentation,impairment of reasoning ability and sleep.15. Hypothermia:(hypothalamus)Alter the equilibrium point of hypothalamic heat-reg mech.such that body temp falls slightly.16.Tolerence,physical dependence and potential for abuse:(locus cerelus)characteristic feature of all opoids.

40 Codeine(1/10 M) Oxycodone and methadone are analogs of codeineFor more presentations and information visitCodeine(1/10 M)Oxycodone and methadone are analogs of codeineCodeine itself has low binding affinity to all of the opioid receptors. Its analgesia producing effects come from its conversion to morphine.When codeine is administered about ten percent is converted to morphine by O-demethylation that occurs in the liver by an enzyme called cytochrome p450.Because of this Codeine is far less potent than morphineIt differs structurally from morphine in that its phenol group is methylated. It is often referred to as methyl-morphine.

41 For more presentations and information visit http://www. pharmaxchangeCodeineCodeine is usually administered orally and it is much more effective orally than morphine (about 60%)Slight sedation,NO euphoria and NO noticeable respiratory depression.Tolerence dev less rapidly and dependence occurs rarely.Uses:CoughDiarrhoeaSomatic pain

42 Heroin(diacetylmorphine) 3MFor more presentations and information visitHeroin(diacetylmorphine) 3MIt is administered through intravenous injections but can also be administered orally or vaporized.It binds most strongly to the mu receptor and is also active in the form of morphine as its acetyl groups are removed.It produces euphoric effects similar to morphine, however, it is thought that these effects are greater and more addicting because of its extremely rapid effect.Its fast action is a result of being extremely lipid- soluble because of its acetyl groups and therefore it immediately crosses the blood brain barrier.

43 For more presentations and information visit http://www. pharmaxchangeHeroinThe use of Heroin causes the body to produce far less of its natural opioid peptides, the endorphins. This creates a dependence on heroin.When a heroin user stops using the drug the withdrawal symptoms are severe.Withdrawal symptoms include anxiety, depression, cramps, vomiting, diarrhea, restless leg syndrome (hence kicking the habit), and a severe sense of pain caused by nothing.Many addicts in withdrawal experience “itchy blood” which can drive the addict to scratch cuts and bruises into his body.

44 B-Benzyl-isoquinolines:For more presentations and information visitB-Benzyl-isoquinolines:1.Papaverine:No analgesic actionRelaxes smooth muscles sp. Of blood vessels.Used in various spastic conditions of arteries of limbs2.Noscapine:V effective cough suppressant. So used instead of codeine.Less addictiveCauses constipation.

45 SYNTHETIC OPOIDS: I.PIPERIDINES:For more presentations and information visitSYNTHETIC OPOIDS: I.PIPERIDINES:Pethidine:Most frequently prescribed opoidStrong agonistPosses most of the effects of morhpine but less histamine release.Also has anti-muscarinic effects of atropineNo constipation and miosisTachycardia(a.muscaranic action)Non-effective anti-tussiveMay cause bronchial dilation so may be given in asthmaLess CNS depressionFor obstetrical analgesia as it doesn’t effect foetus.As an adjunct to anasthesia.(local)

47 Synthetic: phenyh-heptyl amine derivative: Methadone :For more presentations and information visitSynthetic: phenyh-heptyl amine derivative: Methadone :Strong agonistPharmacologically v similar to morphineMethadone is often used to treat heroin addiction because it is a longer lasting opioid.Mild withdrawal effects.

48 For more presentations and information visit http://www. pharmaxchangePropoxyphene:An agonist of kappa-rec and weak agonist of mu and delta.Weaker analgesic than codeine but equally addictiveWell absorbed orallyUsed in combination with aspirin or paracetamol for greater analgesia.No constipation and lesser incidence of N,V,drowsiness and dizziness.For the treatment ofMyalgiaNauralgiaMigrainaArthritis pain.

49 B.Opoids with mixed receptor actions:For more presentations and information visitB.Opoids with mixed receptor actions:1.Phenanthrenes:Nalbuphine:Agonist activity at delta and kappa, and weak antagonist of mu-receptor.Given parenterallyAnalgesia equivalent to morphine with lower abuse potentialAt high dose,ceiling resp. depression.No reversal with naloxoneBuprinorphine:Hign affinity for mu-rec act as partial agonist.Longer duration of actionAs effective in heroine-detoxification as methadone

50 2.Benzomorphans Pentazocine:For more presentations and information visit2.Benzomorphans Pentazocine:A kappa-agonist with weak mu-antagonist activity.Used orally or parenterally(no s/c)Generally effects are similar to morphine but some analgesic effects are due to kappa-rec.High dose cause increase in heart-rate and B.P.Vomitting is less common than with morphine.Patients receiving opoids may experience abstinence synd. when given pentazocine.Used as an analgesic in those with drug-abuse prob.

51 For more presentations and information visit http://www. pharmaxchangeOpioid AntagonistsOpioid Antagonists are used to treat opioid overdose cases.Most are derived from Thebaine (an alkaloid of Opium)The have strong binding affinity for the mu receptorsThey work by competitive inhibition at the binding site (It binds but does not change the receptor while at the same time blocking the agonist).These involves naloxone,naltrexone, and nalmefene.

52 Naloxone: Naloxone is an example of a opioid antagonist.For more presentations and information visitNaloxone:Naloxone is an example of a opioid antagonist.It is administered intravenously.Short duration of actionMetabolized by glucuronidation and excreted in urine.It is a competitive antagonist at mu- delta and kappa rec. with 10 fold higher affinity for mu than kappa.this explains reversal of resp. depression with minimal reversal of analgesia due to kappa.It can rapidly produce the withdrawal symptoms associated with opioid addiction.Naltrexone is another example of an opioid antagonist. It is more potent than Naloxone and is used in the treatment of alcohol addiction but its mechanism in this treatment is unknown.

53 There is no tolerence to antagonist activity. Uses: For more presentations and information visitPharmacodynamics:Almost inert in the absence of agonist but with agonist reverses the effects within 1-3 min .In opoid- addicts it’ll instantaneously precipitate abstinance syndrome.There is no tolerence to antagonist activity.Uses:To treat acute opoid-toxicity.NALTREXONE:is also a pure antagonist and due to long duration it is used as a maintainance drug for addicts in the treatment prog.It is also used for the treatment of chronic alcoholism to decrease craving.Nalmefene:newest agent, derivative of naltrexone,only i/v available.t1/2=8-10 hrs,for opioid overdose.